New benzimidazoles



United States Patent 3,000,898 NEW BENZIMIDAZOLES Karl Hoifmann,Binningen, and Alfred Hunger, Jindrich Kebrle, and Alberto Rossi, Basel,Switzerland, assignors to Ciba Pharmaceutical Products Inc, Summit, NJ.No Drawing. Filed Aug. 31, 1959, Ser. No. 836,923 Claims priority,application Switzerland Sept. 19, 1958 6 Claims. (Ci. 260-30.2)

This invention provides1-tertiary-aminoalkyl-Z-phenylamino-benzimidazoles and salts thereof.

The invention provides more especially benzirnidazoles of the formula fn a in which A represents an alkylene radical, especially a loweralkylene radical, such as the ethylene radical, and R represents a lowertertiary amino group, for example, an alkylene-imino group, which may beinterrupted by a heteroatom, such as a pipen'dino, piperazino,pyrrolidino, morpholino or thiornorpholino group, but preferably adi-loWer-alkyl-amino group the lower alkyl radicals of which contain 1to 6 carbon atoms, and in which R and R each represent a hydrogen atomor an alkyl or alkoxy group, or a nitro group or halogen atom, and Rrepresents a hydrogen atom or an unsubstituted or substitutedhydrocarbon radical, such as an alkyl or aralkyl group e.g. methyl,ethyl, propyl, benzyl carbomethoxy-carboethoxy-orcarbopropoxy-methyl-ethyl or propyl, or an acyl group, more especially alower alkanoyl group such as formyl, acetyl, propionyl or a carbalkoxy,especially a carbo lower alkoxy group, and salts of these compounds.

The new compounds possess a very good analgesic action and inhibitpolysynaptic reflexes; they are therefore useful as analgesics andmuscle relaxants. Of special interest owing to their therapeuticproperties are compounds of the formula G N C2H5 l CHr-CHz-N in which Rhas the meanings given above, R represents an acyl group, especially alower alkanoyl group or a benzyl radical, and R represents a p-loweralkoxy group, and above all l-(fl-diethylaminoethyl)-2-[N-(para-ethoxyphenyl)-N-acetyl-amino] 5 nitro-benzirnidazole, 1(t!-diethylamino-ethyl)-2-[N (pethoxyphenyl)-N-formylamino]-5-nitro-benzimidazole,l-(B-diethylamino-ethyD- Z-[N-(p-ethoxyphenyl) Nbenzyl-amino1-5-nitro-benzimidazole andl-(fi-diethylaminoethyU-Z-[N-(p-ethoxyphenyl) -N-acetyl-amino]-benzimidazole and salts of these compounds.

The new benzimidazoles are obtained by methods in themselves known. Inone process, for example, an amino alkyl group is introduced directly orin stages into the 1-position of a 2-phenylamino-benzimidazoleespecially of a Z-N-acyl or 2-N-benzyl-phenylamino-benzimidazole. Thus,a Z-phenylamino-benzimidazole advantageously on in which the amino groupis substitutedin the manner indicated, may be reacted with a reactiveester of an alcohol of the formula in which A has the meaning givenabove, and R repre sents a tertiary amino group, or a substituentconvertible into such an amino group, for example, a hydroxyl group,and, when the resulting compound contains a substituent convertible intoan amino group, the said substituent is so converted, a hydroxyl group,for example, by chlorination followed by reaction with a secondaryamine. Reactive esters are more especially those of strong inorganic ororganic acids, such as hydrohalic acids or organic sulfonic acids suchas para-toluene sulfonic acid. The reaction is advantageously carriedout in the presence of a condensing agent, especially one which iscapable of forming a metal salt with the benzimidazole, such as analkali metal or alkaline earth metal, for example, sodium, lithium,calcium, or an amide, hydride, hydrocarbon compound, alcoholate, oxideor hydroxide of such metal, for example, sodamide, sodium hydride,lithium butyl, potassium phenyl, lithium phenyl, potassium tertiarybutylate, potassium tertiary amylate, sodium ethylate, sodium oxide orsodium hydroxide, or there may be used a preformed metal salt of thebenzimidazole.

In another process for making the new compounds the benzimidazole ringis formed by subjecting to ring closure a 2(R"-NH) aniline or anN-substitution product thereof, in which R" represents the aforesaidgroup R-A-' or a radical convertible into such group, for example, ahydroxy alkyl group. The substituent convertible into the group RA issubsequently. converted into such group, in the case of a hydroxy-alkylgroup, for example, by chlorination and reaction with a secondary amine.Thus, for example, a Z-tertiary aminoalkyl-amino-aniline may besubjected to ring closure directly or in stages with a phenyl carbamicacid derivative, such as a diphenylurea or diphenyl-thiourea or aderivative thereof, such as an S-substituted isothiourea, or with adiphenyl car-bodiimide.

The reactions may be carried out in the presence or absence of a diluentand/or a condensing agent, and when necessary at a raised temperatureunder atmospheric or superatmospheric pressure.

In the product so obtained a secondary amino group in the 2-position maybe alkylated, aralkylated acylated or carbalkoxylated. A substituent inthe aryl radical may be exchanged for another group, for example, ahydroxyl group for an etherified or esterified hydroxyl group such as alower alkoxy group, or a nitro group for an amino group and the lattergroup exchanged for a halogen atom.

Depending on the procedure used the new compounds are obtained in theform of the free bases or salts thereof. From the salts the free basescan be obtained by reaction with an inorganic base. From the free basessalts can be obtained by reaction with acids suitable for the formationof therapeutically useful salts, for example, hydrohalic acids, sulfuricacid, nitric acid, phosphoric acid, thiocyanic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, analic acid,tataric acid, maleic acid, lactic acid, lysine, leucine, methanesulfonic acid, ethane sulfonic acid, oxyethane sulfonic acid, benzene ortoluene sulfonic acid or a therapeutically active acid. The startingmaterials are known or can be made by methods in themselves known.

The invent-ion also includes any modification of the process in whichthere is used as starting material a compound obtainable as anintermediate product at any stage of the process and the remaining stepsof the process are carried out.

The new compounds can be used as medicaments, for

example, in the form of pharmaceutical preparations which contain thecompound or a salt thereof in admixture with a pharmaceutical organic orinorganic, solid or liquid carrier suitable for enteral, parenteral ortopical administration. For making the carriers there are usedsubstances which do not react with the new compounds or salts thereof,for example, Water gelatine, lactose, starches, magnesium stearate,talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, whitepetroleum jelly, cholesterol or other carrier known for medicaments. Thepharmaceutical preparations may. be, for example, in the form oftablets, dragees, salves orcreams, or in liquid form as solutions,suspensions or emulsions. If desired, they may be sterilized and/ or maycontain auxiliary substances such as preserving, stabilizing, wetting oremulsifying agents, salts for controlling the osmotic pressure orbuffers. They may also contain othertheraputically useful substances.

The following examples illustrate the invention:

Example 1 N CzHs I H2- CHz-N is obtained as a thick oil boiling at180-490 C. under 0.06 Tor.

By dissolving the base in ethanol andmixing the solution with thecalculated quantity of hydrochoric acid in ethanol the hydrochloridemelting at 235237 C. is obtained.

By the same process there can be obtained from 2-(3-diethylamino-ethylamino)-5-nitro-aniline and diphenylcarbodiimide,l-(B-diethylamino-ethyl) 2-phenylamino-5- nitrobenzimidazole of theformula CHPCH N in the form of a crystalline compound melting at 146-147 C., and its hydrochloride melting at 226-227 C.

Example 2 8.5 grams of-2-(,8-diethylamino-ethylamino) -aniline aremixedwith 12.1 grams of S-methyl-sym-diphenyl-isothiourea and themixture is heated for 2 hours at 150 C.., during which a part of theaniline split off distils. The reaction product is dissolved inZN-hydrochloric acid, and the solution is filtered, washed with etherand rendered alkaline with ammonia, and the liberated base is taken upinchloroform. The chloroform solution is washed with sodium carbonate,dried with magnesium sulfate, evaporated and distilled in a bulb tubeunder ahigh vacuum, whereby 1 (15tdiethylaminoethyl)2-phenylamino-benzirnidazole is obtained as a viscous oil boiling at190-200 C. under 0.08 Tor. Its hydrochloride melts at 235-237 C.

By the same process there can be obtained from 2-(5-diethylamino-ethylam-ino)-5-nitroaniline and S-methylsymdiphenylisothiourea, l (ediethylaminoethyD-Z- phenyl-amino-S-nitro-benzimidazolein the form. of a crystalline compound melting at 146l47 C., and,itshydrochloride melting at 226-227 C.

By the same process there can also be obtained from2-(B-diethylamino-ethylamiuo) -aniline andS-methyl-symdi-(para-methoxyphenyl)-isothiourea,l-(fi-diethylam-inoethyl)-2-(para-methoxyphenylamino) benZim-idazole ofthe formula GHFOHI-N as a crystalline compound melting at 116ll7 C., andits hydrochloride melting at 223224 C.

By using as starting materials 2-(fi-diethylaminoethylamino) aniline andS methyl-sym-di-(paraethoxyphenyl)-isothiourca, there is obtained by thesame process 1- (;8-diethylarruno-ethyl) -2-(para-ethoxyphenylamino)-benzimidazole of the formula and its hydrochloride melting at 197-198C.

In an analogous manner there can be obtained by reacting2'-(B-diethylamino-ethylamino) -5- nitro aniline withS-methyl-sym-di-(para-methoxyphenyl)-isothiourea- 1-(B-diethylaminoethyl) -2-( para. methoxyphenylarninoS-nitro-benzimidazole of the formula I]\T CzHs CHPCHPN CzHu as acrystalline powder melting at -116" C., and its hydrochloride melting at240-241 C.

By using as starting materialsZ-(fi-diethylamino-ethylarnino)-5-nitro-aniline andS-methyl-sym-di-(para-ethoxyphenyl)-isothiourea the same process leadsto l-(p-diethylaminoethyD-Z- (para-ethoxyphenyl-amino)-5-nitrobenzimidazole of the formula CzHs intheform of a crystallinecompound melting: at 124-- 125- C- of which the. hydrochloride melts atl95'196 C. By reactingv Z-(fl-diethylamino-ethylamino)-5.-chlorani linebythe sameprocess with S-methyl-sym-di-(paraethoxyphenyl)-isothiou-rea-there is obtained l-(fl-diethyl-- CHz-CHz-N CzHt of whichthe hydrochloride melts at 166-170 C.

The S-methyl-sym-di-(para-methoxyphenyl)-isothiourea can be prepared inthe following manner:

98.4 grams of para-ansidine, 60 grams of carbon di sulfide and 4 gramsof sulfur are boiled under reflux in 400 ml. of alcohol for 2 hours. Thealcoholic solution is concentrated to crystallizesym-di-(para-methoxyphenyl)-thiourea melting at l83 184 C.

10.2 grams of the latter compound are dissolved in 100 ml. of acetone,5.7 grams of dimethylsulfate are added dropwise at room temperature,while stirring, and the mixture is boiled for 4 hours under reflux. Thereaction mixture is evaporated, and mixed with ice water, renderedalkaline with sodium carbonate and extracted with chloroform. Afterbeing dried with magnesium sulfate, the chloroform solution isconcentrated, whereby S-methyl-sym-di-(para-methoxyphenyl)-isothioureamelting at 74-76 C. crystallizes out.

By using phenetidine and carbon disulfide as starting materials there isobtained by the same process sym-di- (para-ethoxyphenyl)-thioureamelting at 170 C. Its S- methyl-derivative melts at 9395 C.

Example 3 N O=CCH3 OzN I NQ-O CaHs CHrCHz-N By treating a methanolicsolution of the base with the calculated quantity of alcoholichydrochloric acid there is obtained the crystalline hydrochloridemelting at 220- 222 C.

By usingl-(fi-diethylaminoethyl)-2-(para-ethoxy+phenylamino)-benzimidazole asstarting material in the same process there is obtainedl-(fi-diethylaminoethyh- Z-[N-(para-ethoxyphenyl) -N-acetyl amino]benzimidazole of the formula CHr-CHFN o=cl:-om Q OaHs Its hydrochloridemelts at 198-199 C.

6 Example 4 A mixture of 22.1 grams ofZ-(B-diethyIamin'G-ethylamino)-5-methyl-aniline and 33.5 grams ofS-methylsym-di-(p-ethoxyphenyl)-iso-thiourea is .heated for 10 hours atISO- C. The reaction product is dissolved in ZN-hydrochloric acid, thesolution filtered, Washed with ethyl acteate, rendered alkaline withammonia and the liberated base taken up in ether. The ethereal solutionis washed with water, dried with magnesium sulfate, evaporated anddistilled in a bulb tube, l-(fi-diethylaminoethyl) -2-(p-ethoxy-phenylamino) 5 methyl-benzimidazole of the formula N OHU iCHPOHPN Nit-Q0 01H.

being obtained as a viscous oil boiling at 220-230 C.

under 0.01 mm. of pressure. hydrate melts at 1l6-117 C.

Example 5 10.6 grams ofl-(B-diethylaminoethyl)-2-(p-ethoxyphenylamino)-5-methyl-benzimidazoleare dissolved in 65 ml. of glacial acetic acid and treated with 4.2 ml.of acetic anhydride. The mixture is boiled under reflux for Itsdihydrochloride-mono- 4 hours, evaporated and the residue taken up inWater,

rendered alkaline with ammonia and the liberated base taken up inchloroform. The chloroform solution is washed with sodium carbonate,dried with magnesium sulfate and evaporated. The faintly brown, oilyresidue is 1-( B-diethylamino-ethyl)-2-[N- (p-ethoxy phenyl) N-acetylamino]-5-methyl-benzimidazole of the formula CzH5 On treating thealcoholic solution of the base with the calculated quantity of alcoholichydrochloric acid there is obtained the crystallized hydrochloride whichafter being recrystallized from a mixture of methanol and ether melts at209210 C.

Example 6 melting at 163-166 C. is obtained.

By reacting the alcoholic solution of the base with the calculatedquantity of alcoholic hydrochloric acid there is obtained thehydrochloride melting at 165-169 C,

being obtained as faintly yellow crystals melting at 132.- 134 C.

Example 8 14.5 grams ofI-(fi-diethylamino-ethyl)-2-phenylarninobenzimidazole are boiled in 40ml. of glacial acetic acid with 7.05 ml. of acetic anhydride for 6 hoursunder reflux. The reaction mixture is then evaporated in vacuo, the

residue taken up in water, rendered alkaline with arm monia and theliberated base extracted with chloroform. The chloroform solution isWashed with sodium carbonate solution, dried over magnesium sulfate andevaporated. The resulting 1-( B diethylamino ethyl)-2- (phenyl-N-acetyl-amino) -benzimidazole of the'formula distills in a bulb tube at170-180 C. under 0.2 mm. of pressure. Its hydrochloride melts at118-119" C.

By the same process there'is' obtained from l-(fi-diethylamino-ethyl) 2(p methoxy phenylamino) benzimidazole- 1 (B diethyla-mino ethyl-)-2['N-(p-methoxy phenyl) -N-acetyl amino] benzimidazole of the formula/N\O=(JCH3.

NI /G2Hs CHi-OH2N CzHs melting at 95-96 C. Its hydrochloride melts at180- 182 .0.

Starting froml-(fi-diethylamino-ethyl)-2-(p-methoxyphenylamino)--nitro-benzimidazolethere is obtained by the same process 1.-([3-diethyla-mino.-ethyl)-2-[N- (p-methoxy-phenyl)-N-acetyl-amino] -5-nitro-benzimidazole oftheformula N O=OCHs OzN i N OCH. \N CHs CHr-CH2-N CzHs melting at 90-91. C.Its hydrochloride melts at 219- 220? C. 7

Starting from l-(fi diethylamino-ethyl)-2-phenylamino-S-nitIo-benzimidaaole there is obtained by the same process 1 (,8diethylamino ethyl) 2 (N-phenyl-N acetylamino)-5-nitro-benzimidazole ofthe formula asa viscous oiI',.-thehydrochloride of which melts at 219-220 C.

Example 9" 10.7 grams of 1.-(,3-diethylamino-ethy1)-2-phenylamino.benzimidazole are heated in- 50 ml. of propionic acid with 6.75 grams ofpropionic acid anhydride for. 6 hours at 120 C. The reaction mixture is;then: evaporated in vacuo,- the: residuev taken up in water, renderedalkaline with ammonia. and extracted with chloroform. The chloroformsolution is washed with sodium carbonate solution, dried over.magnesiumsulfate and evaporated. The resulting. 1v (fldiethylaminoethyl) -2-(N-pheny1-N-propionylraminoz);-benzimidazole of the formula isconverted into its hydrochloride melting at 192-193 C.

1 (/3 diethylamino ethyl) 2 (p methoxy --ph'enylamino) -benzi-midazolecan be converted by the same process into 1' (B- diethyl'amino ethyl)-2- [N-(p-methoxyphenyl) -N-propionylamino] -benzimidazole ofthe formulamelting at 105-106 C., the hydrochloride of which melts at 224-225 C.

1 (B diethylamino ethyl) 2 phenylamino 5- nitro-benzimidazole'can' beconverted by the same process into1-(B-diethylamino-ethyl)-2-(N-phenyl-N-propionylamino)-5-nitro-benzimidazo1eof the formula N O=CCH2CHa OzN 0 i orm CHr-CHz-N C2115 melting at102-103 C. Its hydrochloride melts. at 200- Example 10 15 grams ofl-(B-diethylamino-ethyl)-2-(paraethoxyphenyl) -5-nitro-benzimidazole aredissolved in a mixture consisting of 10.2 grams offormic acid and 24.6grams of acetic anhydride which mixture has previously been heated to 60C., and the reaction mixture maintained at 60 C. for 6 hours. Afterevaporating in vacuo', the residue is agitated with a mixture of ml. ofether and 25 m1. of aqueous sodium carbonate until the whole dissolves.The ethereal. extract is dried and evaporated to a volume of 15 ml. Oncooling, l-(B-diethylaminospouses ethyl) 2 [N (p ethoxy phenyl). Nformylethyl)2-[N-(p-ethoxy-phenyl)-N-(carbethoxy methyl}aminol-S-nitro-benzimidazole of the formula amino]-5-nitro-benzimidazole of the formula OaN I N N-Q-Msm 5 OHN NQO CsHs NCH: lHPCHPN f 02115 CHz-OHz-N which melts at 102 c., crystallizes out.The hydrochloride of this base melts at 225-228? C. which as base meltsat 96-98 C. and in the form of its Example 11 hydrochloride at 169--171C. By an analogous process to that described in Example 15 Example 1516, from 8 grams of -(l l 3 -(P- Y- By an analogous process to thatdescribed in Example phenylamino)-5-nitro-benzimidazole, 0.53 grams ofsodi- 16, from 12 grams of l-(B-diethylamino-ethyl)-2-(p-ethum hydrideand 2.03 grams of propionylchloride indioxy-phenylamino)-5-nitro-benzimidazole, 0.8 gram of oxane solutionthere is obtained l-(fi-diethylamino-ethynsodium hydride and 3.8 gramsof benzyl chloride in di- 2 [N (p ethoxyphenyl) N propionyl amino] 5-oxane solution there is obtained l-(B-diethylarnino-ethyl)-nitro-benzimidazole of the formula Z-[N-(pethoxy-phenyl)-benzylamino]-5-nitro-benzimid- N 0=C CH2CH3 azole of theformula CaHs /C2H5 which as free base melts at 113-115 C. and in theform CHz-CHz-N of its hydrochloride at 230-235 C. 02115 Example 12 whichin the form of its dihydrochloride melts at 196- By an analogous processto that described in Example 198 C. 16, from 12 grams ofl-(fi-diethylamino-ethyl)-2-(p-eth- Example 16oxy-phenylamino)-5-nitro-benzimidazole, 0.8 gram of sodium hydride and4.7 grams of benzoyl chloride in dioxane solution there is obtainedl-(B-diethylaminoethyl) 2 [N-(p-ethoxyphenyl) N benzoy1amino1-5-nitro-benzimidazole of the formula 4 12 grams ofl-(B-diethylamino-ethyl)-2-(p-ethoxyphenylamino)-5-nitro-benzimidazoleare dissolved in 75 ml. of dioxane, 0.8 gram of sodium hydride is addedto the solution and the deep blue solution heated at 60 C. with stirringuntil the evolution of hydrogen practically N 0=0CsH5 ceases. 5.3 gramsof ethyl iodide dissolved in 5 ml. of 02N 1 dioxane are added dropwiseat the above temperature, N-QO C2115 and the reaction mixture stirredfor half an hour at 100 C.; the solvent is then evaporated in vacuo. Theresidue is taken up in 3040 ml. of ether, the ethereal solution GHPCHFNallowed to stand in a refrigerator, filtered oil from the 0235 startingmaterial which crystallizes out; 9.5 ml. of 3.12N-

a alcoholic hydrochloric acid are added and the reaction which in theform of its hydrochloride melts at 249-250 mass h evaporated to drynessThe Smohtained C drochloride of l-(B diethylamino-ethyl)-2-[N-(p-ethoxy-Example 13 pheny1)-ethylamino] -5-nitro-benzimidazole of the formula Byan analogous process to that described in Example N 0 16, from 12 gramsof l-(fiy y '(P- (MN oxy-phenylamino)-5-nitro-benzimidazole, 1.2 gramsof N 002115 sodium hydride and 3.3 grams of chloroformic acid ethylester in dioxane solution there is obtained l -(fi-diethyl- N 02Hamino-ethyl)-2-[N-(p-ethoxy-phenyl) N carbethoxyamino1-5-nitro-benzimidazole of the formula CHPCH" N N O=CC2H5 L 0 C His recrystallized from isopropanol for the purpose of puri- 2 5 ficationand melts at 17 8179 C. rlI CzHs Example 17 CHz-CHz-N 5 9.55 grams ofZ-(p-methoxy-phenylamino)-benzimidazole are stirred in 100 ml. ofabsolute dioxane with CH? 115 f d' hd'd t90C til furth gramso solumyrle-a .un no er ghlch m the form of its hydrochloride melts at 196 197evolution of gas can be detected grams of ammo? Ex m le 14ethyl-diethylamine are then added dropwise at 60 C., a p and the wholeis stirred for 14 hours at 60 C. The reac- By an analogous process tothat described in Example tion mixture is then suction-filtered, thefiltrate evapo- 16, from 12 grams ofl-(fi-diethylamino-ethyl)-2-(p-ethrated under reduced pressure, theresidue taken up in oxy-phenylamino)-5-nitro-benzimidazole, 0.8 gram ofdilute hydrochloric acid, the solution extracted with ether sodiumhydride and 6 grams of bromacetic acid ester in and rendered alkalineagain with ammonia solution. The

dioxane solution there is obtained l-(p-diethyIamiuQ- liberated base istaken up in chloroform, washed with sodium carbonate solution, driedover magnesium sulfate and evaporated. The residue recrystallized fromether yields pure1(B-diethylaminO-ethyl)-2-(p-methoxy-phenylamino)-benzimidazole meltingat l16-117 C.

The 2-(p-methoxy-phenylamino)-benzimidazole used as starting materialcan be prepared as follows:

32.4 grams of o-phenylene-diamine and 81.6 grams of S-methyl-sym-di-(pmethoxy-phenyl) isothiourea are heated for 15 hours at 160 C.,methyl-mercaptan being liberated. By crystallizing the reaction mixtureZ-(pmethoxy-phenyl-amino) -benzimidazole melting at 177- 178 C. isobtained.

Example 18 5.62 grams of 2 [N-(p-methoxy-phenyl)-N-acetylamino]-benzimidazole are stirred under refluxin 50 m1. of absolute dioxane with 0.8 grams of sodium hydride until nofurther evolution of gas is detectable. 4.1 grams ofB-chlorethyl-diethylamine are then added dropwise and the whole isstirred for 14 hours at 60 C. The mixture is then suction-filtered, thefiltrate evaporated under reduced pressure, the residue taken up indilute hydrochloric acid, extracted with ether and rendered alkalineagain with dilute ammonia. The liberated base is taken up in chloroform,Washed with sodium carbonate solution, dried over magnesium sulfate andevaporated. The residue recrystallized from ether yields purel-(fl-diethylaminm ethyl) -2-[N- (p-methoxy-phenyl)-N-acetyl-amino]benzimidazole melting at 95-96 C.

The 2- [N- (p-methoxy-phenyl -N-acetyl-amino] -benzimidazole used asstarting material can be prepared as follows:-

9.55 grams of 2-(p-methoxy-phenylamino)-benzimidazole are boiled with5.7 ml. of acetic anhydride and 30 ml. of glacial acetic acid for 14hours, concentrated under reduced pressure, diluted with ether andsuctionfiltered. The resulting acetyl derivative melts at 173- 175 C.

Example 19 9 grams of 2-(,B-dimethylamino-ethylamino)-aniline and 12.1grams of S-methyl-di-(p-ethoxy-phenyl)-isothiourea are heated togetherfor 3 hours at 160 C., any methyl-mercaptan formed being removed. Thereaction product is dissolved in ZN-hydrochloric acid, the solutionwashed with ether, rendered alkaline with ammonia and the liberatedbasetaken up in chloroform. The chloroform solution is washed with sodiumcarbonate solution and dried over magnesium sulfate and, afterbeingevaporated and recrystallized from a mixture of acetone, ether andpentane, yields l-(B-dimethyl aminoethyl)-2-(pethoxy-phenylamino)-benzimidazole of the formula U -NHQOC2HE melting at95-96 C. The hydrochloride melts unsharply between 90 and 155 C.

Example 20 1112 grams of 2-(fl-dimethylamino-ethylamino) --nitroanilineare heated with 12.1 grams of S-methyLdi-(pethoxy-phenyl)-isothioureafor3 hours at 150-160 C., any methyl-mercaptan formed being removed. Thereaction product is dissolved in ZN-hydrochloric acid, the solutionwashed with ether, rendered' alkalin'e' with emmonia and the liberatedbase taken up in chloroform. The chloroform'solution is washed withsodium carbonate solution and dried over magnesiumisulfat'e, evaporatedand recrystallized from a mixture of acetone and ether' 12 to yieldl-(fi-dir'nethylamino-ethyl)-2-(p-ethoxy-phenylamino)-5-nitro'-befizimidazole 6f the formula melting at. 153-154" C. Thehydrochloride melts at 240-241 C. 7

Example 21 1.8 grams ofl-(fi-dimethylamino-ethyl)-2-(p-ethoxyphenylamino 5-nitro-benzimidazoleare boiled under reflux in 20 m1. of glacial acetic acid with 0.7 ml. ofacetic anhydride for 12 hours, evaporated, the residue taken up inwater, rendered alkaline with ammonia solution and the liberated basetaken up in chloroform. The chloroform solution is washed with sodiumcarbonate solution and dried over magnesium sulfate, evaporated andrecrystallized from ether to yield l-(fi-dimethylamino-ethyl)-2[N-(p-ethoxy-phenyl)-N-acetyl-amino]- 5-nitro-benzimidazole of theformula N o=o-om OQN I N-QOChEh melting at 137-138" C. The hydrochloridemelts at 199- 200 C.

Example 22 5 grams of l-(fl-dimethylamiuo-ethyl)-2-(p-ethoxyphenylamino)-benzimidazole are boiled in 50 ml. of glacialacetic acid with 2.15 ml. of acetic anhydride for 12 hours, evaporated,the residue taken up in water, rendered alkaline with ammonia solutionand the liberated base taken up in chloroform. The chloroform solutionis washed with sodium carbonate solution, dried over magnesium sulfate,evaporated and recrystallized from ether to yield 1(fl-dimethylamino-ethyl) 2 [N-(p-ethoxyphenyl)-N-acetylamino]-benzimidazole of the formula .L OCa melting at 89-90 C. Thehydrochloride melts at 224- 225 C.

What is claimed is:

1. A member selected from the group consisting of benzimidazolesof theformula UNITED STATES PATENT OFFICE CERTIFICATE OF CURRECTION Patent No.3,000,898 I d Q September-l9{-1961 Karl Hoffmann et, al. v

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

formula, for

Column 1, lines 45 to 54, upper right-hand portion of the 2 read column41, line 7, for""""symdiphenyl" read sym=diphenyl g column 6, line 6,for ethyl acteate" read ethyl acetate -g column 9, lines 60 to 66, forthat portion of the formula reading O C -C H v I I 0=C0C H read N MNSigned and sealed this l0th (ll-a5} of July 1962.

(SEAL) Attest:

ERNEST w. SWIDER' -DAVID L. LADD Attesting Ufficer Commissioner ofPatents

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF BENZIMIDAZOLES OF THEFORMULA